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Nanophthalmos is a rare ocular disorder characterized by a small, structurally normal eye with markedly reduced axial length and severe hyperopia. The PRSS56 gene encodes a secreted trypsin-like serine protease expressed in the retina, sclera, and optic nerve, and is implicated in global ocular growth regulation. Biallelic and, more recently, monoallelic variants in PRSS56 have been reported in multiple ethnic cohorts, linking loss-of-function and missense changes to nanophthalmos pathogenesis. This summary reviews genetic and functional data supporting a definitive gene–disease relationship between PRSS56 and nanophthalmos.
Genetically, PRSS56-related nanophthalmos follows predominantly autosomal recessive inheritance. In trio-based WGS of 11 Chinese probands, deleterious PRSS56 variants—including canonical splice-site changes (c.849+1G>C, c.849+1G>T), nonsense (c.1258G>T (p.Gly420Ter)), and frameshifts (c.1573del (p.Val525fs), c.1066del (p.Gln356fs), c.353G>A (p.Trp118Ter))—were identified in eight affected individuals ((PMID:31266062)). A consanguineous Roma family exhibited pseudodominant inheritance of a homozygous missense variant c.1509G>C (p.Met503Ile) segregating in two affected relatives ((PMID:32454992)). Founder analyses in Tunisian families revealed a recurrent c.1059_1066insC indel in six pedigrees, consistent with a 1,850-year-old haplotype ((PMID:23820083)). Additional frameshift and splice variants have been reported in European and Japanese cohorts, confirming broad allelic heterogeneity.
Case reports and series encompass over 45 probands from at least eight unrelated families across diverse populations, with variant types including missense, nonsense, splice, and frameshift changes. A notable allele, c.1258G>T (p.Gly420Ter), recurs in unrelated Chinese probands ((PMID:31266062)). Compound heterozygotes and homozygotes have been described in both isolated nanophthalmos and posterior microphthalmos, with axial lengths consistently below 17 mm. Although most PRSS56 variants obey a recessive pattern, heterozygous truncating variants c.781G>A (p.Gly261Arg) and c.1066dup (p.Gln356ProfsTer) were associated with dominant nanophthalmos in a small Chinese pedigree ((PMID:35383051)).
Segregation data include co-segregation of pathogenic alleles in multiple affected relatives: two in a Roma family and five in posterior microphthalmos pedigrees totaling seven additional relatives across studies. Many reports feature complete penetrance among homozygotes or compound heterozygotes without extraneous ocular phenotypes.
Functional studies support haploinsufficiency as the primary mechanism. Three pathogenic missense variants (p.Arg176Gly, p.Trp309Ser, p.Gln356fs) and a Tunisian founder frameshift c.1066dupC abolish enzymatic activity, as shown by molecular modeling and reduction of serine-type endopeptidase function in overexpression assays ((PMID:21397065); PMID:35383051). PRSS56 transcript is detected in human ocular tissues and in mouse eye from embryonic day 17 onwards, consistent with a developmental role. Cellular models of mutant PRSS56 demonstrate mislocalization and impaired enzymatic activity, linking genotype to hyperopic phenotype.
No significant conflicting evidence has been reported beyond variable expressivity in heterozygotes, and all pathogenic variants demonstrate concordant biochemical defects. While additional modifiers may exist, current data robustly support PRSS56 loss-of-function as causative for autosomal recessive nanophthalmos and rare dominant presentations.
Overall, genetic and functional concordance across multiple cohorts, segregation in families, and mechanistic assays fulfill ClinGen criteria for a Strong gene–disease association. PRSS56 sequencing enables molecular diagnosis, carrier screening, and informed genetic counseling in nanophthalmos. Key take-home: PRSS56 variant analysis should be included in diagnostic panels for early identification and management of nanophthalmos.
Gene–Disease AssociationStrongOver 45 probands across ≥8 unrelated families, multi-family segregation, founder haplotype evidence, concordant functional data Genetic EvidenceStrongNumerous biallelic LoF and missense variants in >20 probands reaching genetic evidence cap Functional EvidenceModerateIn vitro enzymatic assays and transcript expression confirm loss-of-function mechanism |